Immuno-Oncology: An Evolving Approach to Cancer Care
Review a downloadable slide deck by Thomas F. Gajewski, MD, PhD, covering the most clinically relevant new data reported from Immuno-Oncology: An Evolving Approach to Cancer Care.
Target Audience
This activity is designed to meet the educational needs of oncologists and other healthcare professionals involved in cancer care.
Format: Microsoft PowerPoint (.ppt) | File size: 26.2 MB | Date posted: 6/20/2012
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This slide deck in its original and unaltered format is for educational purposes and is current as of June 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CE provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
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This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
Immuno-Oncology: An Evolving Approach to Cancer Care
1.
2. DISCLAIMER
This slide deck in its original and unaltered format is for educational purposes and is
current as of June 2012. All materials contained herein reflect the views of the
faculty, and not those of IMER, the CME provider, or the commercial supporter. These
materials may discuss therapeutic products that have not been approved by the US
Food and Drug Administration and off-label uses of approved products. Readers
should not rely on this information as a substitute for professional medical advice,
diagnosis, or treatment. The use of any information provided is solely at your own risk,
and readers should verify the prescribing information and all data before treating
patients or employing any therapeutic products described in this educational activity.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be
used for personal, non-commercial presentations only if the content and references
remain unchanged. No part of this slide deck may be published in print or
electronically as a promotional or certified educational activity without prior written
permission from IMER. Additional terms may apply. See Terms of Service on
IMERonline.com for details.
3. DISCLAIMER
Participants have an implied responsibility to use the newly acquired information
to enhance patient outcomes and their own professional development. The
information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis
or treatment discussed or suggested in this activity should not be used by
clinicians without evaluation of their patients’ conditions and possible
contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.
DISCLOSURE OF UNLABELED USE
This activity may contain discussion of published and/or investigational uses of
agents that are not indicated by the FDA. PIM and IMER do not recommend the
use of any agent outside of the labeled indications.
The opinions expressed in the activity are those of the faculty and do not
necessarily represent the views of PIM and IMER. Please refer to the official
prescribing information for each product for discussion of approved indications,
contraindications, and warnings.
4. Disclosure of Conflicts of Interest
Thomas F. Gajewski, MD, PhD, reported a financial interest/relationship or affiliation
in the form of: Consultant, Amgen, Bristol-Myers Squibb Company, GlaxoSmithKline
plc, Merck & Co., Inc., Roche Pharmaceuticals, Inc.; Contracted Research, Bristol-
Myers Squibb Company, CureTech Ltd., GlaxoSmithKline plc, Morphotek, Inc.,
Roche-Genentech.
Charles G. Drake, MD, PhD, reported a financial interest/relationship or affiliation in
the form of: Royalty, Amplimmune, Inc., Bristol-Myers Squibb Company; Receipt of
Intellectual Property Rights/Patent Holder, Amplimmune, Inc., Bristol-Myers Squibb
Company; Consultant, Amplimmune, Inc., Bristol-Myers Squibb Company, Dendreon
Corporation, ImmuneXcite, Inc.; Ownership Interest, Amplimmune, Inc.
John Powderly II, MD, CPI, reported a financial interest/relationship or affiliation in
the form of: Receipt of Intellectual Property Rights/Patent Holder, BioCytics, Inc.;
Consulting Fees, Amplimmune, Inc., Bristol-Myers Squibb Company, Genentech
BioOncology; Speakers Bureau, Bristol-Myers Squibb Company; Contracted
Research, Amplimmune, Inc., Bristol-Myers Squibb Company, Genentech
BioOncology; Company Ownership Interest, BioCytics, Inc.
Michael B. Atkins, MD, reported a financial interest/relationship or affiliation in the
form of: Consultant, AstraZeneca Pharmaceuticals LP, AVEO Pharmaceuticals, Inc.,
Bristol-Myers Squibb Company, Genentech BioOncology, Prometheus.
5. Welcome and Activity
Overview
Thomas F. Gajewski, MD, PhD
The University of Chicago Medicine
6. Learning Objectives
L
Upon completion of this activity, participants
should be better able to:
Enhance knowledge on the biological foundations of immuno-
oncology approaches to the treatment of cancer
Describe the roles, targets, and mechanisms of action of novel and
emerging immuno-oncologic agents
Evaluate new safety and efficacy data on recently approved and
emerging immuno-oncologic agents across tumor types
Identify unique patterns of clinical response in patients treated with
immuno-oncologic agents
Monitor and manage immune-related adverse effects associated
with immuno-oncologic agents
Describe how new immuno-oncologic agents are being integrated
into existing treatment evidence-based guidelines
7. Activity Agenda
7:30 – 7:35 pm Welcome and Activity Overview
7:35 – 7:50 pm Immuno-Oncology: Understanding the Biological
Foundations of the Immune System in Cancer
7:50 – 8:10 pm Melanoma: A Classic Tumor Model for Immunotherapy
8:10 – 8:25 pm The Evolving Role of Immunotherapy for Prostate Cancer
8:25 – 8:40 pm The Emerging Role of Immunotherapy for Lung Cancer
8:40 – 8:55 pm Emerging Immunotherapies for Renal Cell Carcinoma
8:55 – 9:15 pm Interactive Case Studies: Applying Current
Immunotherapies Into Practice
9:15 – 9:25 pm Expert Panel Perspectives: Placing Current and
Emerging Immunotherapies in Clinical Context
9:25 – 9:30 pm Questions & Answers and Activity Conclusion
9. The Genetic Instability of Cancer Cells Creates
Antigens That Can Be Recognized by the
Immune System
Normal cell presents self peptides
bound to MHC molecules
New peptides
created by
mutation
or increased
expression Normal cell
A point mutation in a self protein allows A point mutation in a self peptide creates
binding of a new peptide to MHC molecules a new epitope for recognition by T cells
Tumor cell Tumor cell
MHC = major histocompatibility complex.
www.immunoweb.com/tu10.htm
10. Generation of Tumor Antigens
Point mutations in normal genes
Overexpressed normal genes
Molecular mishaps (reverse strand, intron sequences,
alternative splicing)
Embryonic genes
Tissue-restricted differentiation antigens
Translocation fusion proteins
Viral genes
Alternative glycosylation
11. Two Principal Means to Promote
Immune-Mediated Tumor Destruction:
Cytolytic T Lymphocytes and Antibodies
NK = natural killer.
12. CD8+ Cytotoxic T Lymphocyte Killing
an Antigen-Expressing Tumor Cell
How Do These CD8+ T Cells Initially Become Activated to Fight Tumors?
TCR = T-cell receptor.
Boissonnas et al, 2007.
13. T Cells Traffic Between the Tissues,
Lymphatics, and the Blood in Two Major
Differentiation States
Lymphocytes and Naïve lymphocytes
lymph return to blood enter lymph nodes
via thoracic duct from blood
heart
Lymph node
Antigens from sites of
Infected
infection reach lymph Tumor
peripheral
nodes via lymphatics
tissue
Janeway et al, 2001.
14. Dendritic Cells (DCs) Pick Up Antigens From
Infected Tissues and Migrate to Lymph Nodes
Antigen uptake by Langerhans’ cells leave the skin
Langerhans’ cells in the skin and enter the lymphatic system
Langerhans’ cells enter the
B7-positive dendritic cells
lymph node to become dendritic
stimulate naïve T cells
cells expressing B7
Discovery of dendritic cells by Ralph
Steinman earned Nobel Prize in 2011
Banchereau et al, 1998.
15. The Main Costimulatory Receptor on
T Cells is CD28, Which Binds to
B7-1/B7-2 on Activated Dendritic Cells
T cell
TCR/CD3 CD28
complex
CD4
B7.1
or
B7.2
APC MHC class II
APC = antigen presenting cell.
Janeway et al, 1996; Topalian et al, 2011.
16. Model for CD8+ T-Cell-Mediated Anti-Tumor
Immune Response In Vivo
MHC I MHC II Immature DC
Migration From
Tumor
Tumor granzymes
TCR
eCD8
B7
APC
Mature DC
Lymph Node
eCD8
nCD8 Migration From
Migration to
Lymph Node Lymph Node
CD28
IL-2
Harlin et al, 2009; Gajewski et al, 2006.
17. Theoretical Reasons for Failure of Immune
System to Prevent Cancer Outgrowth
Failure to activate specific T cells
– Inadequate antigen processing/presentation
– Insufficient T-cell repertoire
– Available T cells below activation threshold setpoint
Ineffective T-cell differentiation into effector cells
Inadequate expansion of T cells to needed frequency
Lack of homing of primed T cells to tumor sites
Immunosuppression in tumor microenvironment
– CTLA-4 on T cells (inhibitory receptor)
– PD-1 on T cells (binds PD-L1 on tumor cells)
– T-cell anergy (deficient B7 costimulation)
– CD4+CD25+FoxP3+ Tregs (extrinsic suppression)
– Indoleamine-2,3-dioxygenase (IDO tryptophan catabolism)
Gajewski et al, 2007; Zou, 2005.
18. Model for CD8+ T-Cell-Mediated Anti-Tumor
Immune Response In Vivo: Interventions
TLR ligands Blockade of
suppression
MHC I MHC II Immature DC
Migration From
Tumor
Vaccines
Tumor granzymes
TCR
eCD8
B7
Costimulation
APC
Mature DC Cytokines
Chemokines
Lymph Node
eCD8
nCD8 Migration From
Migration to
Lymph Node Lymph Node
CD28
IL-2
Harlin et al, 2009; Gajewski et al, 2006.
19. Model for CD8+ T-Cell-Mediated Anti-Tumor
Immune Response In Vivo: Interventions (cont.)
TLR ligands Blockade of
suppression
MHC I MHC II Immature DC
Migration From
Tumor
Vaccines
Tumor granzymes
TCR
eCD8
B7
Costimulation
APC
Mature DC Cytokines
Chemokines
Lymph Node
eCD8
nCD8 Migration From
Migration to
Lymph Node Lymph Node
CD28
IL-2
Harlin et al, 2009; Gajewski et al, 2006.
20. Toll-Like Receptors (TLRs)
First identified in Drosophila as receptor recognizing
pathogens for innate immunity
At least 11 mammalian homologues identified
Expressed on DCs and other APCs
Mediate activation and maturation of APCs to render
them optimal for T-cell activation
Ligands should be excellent vaccine adjuvants
Discovery of Innate Immune Sensing Systems by
Bruce Beutler and Jules Hoffmann Earned Nobel Prize in 2011
Takeda et al, 2004.
21. TLR Pathway
Plants Drosophila Mammals
PAM
P
Protease
PAM
Spätzle P IL-1
Toll TLR4 IL-1R
Extracellular
Pathogen
Cytoplasm or PAMP MyD88 TIRAP MyD88 MyD88
RPP5,
N, L6
Immune response Immune response Immune response
Triggers activation of dendritic cells and other APCs
Medzhitov et al, 2001.
22. Imiquimod for Basal Cell Carcinoma (BCC)
Imiquimod is a TLR7 agonist that activates DCs
Randomized clinical trial done in patients with BCC
100% RR with BID dosing compared to 19% with vehicle
alone!
Also active on warts and cutaneous metastases of
melanoma
Other TLR ligands are in clinical trials, including CpG 7909
(TLR9 agonist)
TLR agonists being combined with tumor antigens in
cancer vaccines (eg, GSK-Bio MAGE3 vaccine)
RR = response rate.
Sapijaszko, 2005; Goldman et al, 2009.
23. Key Takeaways
CD8+ T cells can recognize neoantigens expressed by
tumor cells
In order for antigen-specific T cells to become activated
to differentiate into cytolytic effector cells, they need to
be stimulated by activated DCs in lymph nodes
DCs must be activated via innate immune sensing
pathways (TLRs)
Activated CTL recirculate and traffic tumor tumors where
they have a chance to destroy cancer cells
In cancer, failure can occur at various stages of this
process, which generates multiple opportunities for
therapeutic intervention
CTL = cytotoxic T lymphocyte.
24. Melanoma: A Classic Tumor
Model for Immunotherapy
Thomas F. Gajewski, MD, PhD
The University of Chicago Medicine
25. Model for CD8+ T-Cell-Mediated Anti-Tumor
Immune Response In Vivo: Interventions (cont.)
Blockade of
suppression
MHC I MHC II Immature DC
Migration From
Tumor
Vaccines
Tumor granzymes
TCR
eCD8
B7
Costimulation
APC
Mature DC Cytokines
Chemokines
Lymph Node
eCD8
nCD8 Migration From
Migration to
Lymph Node Lymph Node
CD28
IL-2
Harlin et al, 2009; Gajewski et al, 2006.
26. Model for CD8+ T-Cell-Mediated Anti-Tumor
Immune Response In Vivo: Interventions (cont.)
Blockade of
suppression
MHC I MHC II Immature DC
Migration From
Tumor
Vaccines
Tumor granzymes
TCR
eCD8
B7
Costimulation
APC
Mature DC Cytokines
Chemokines
Lymph Node
eCD8
nCD8 Migration From
Migration to
Lymph Node Lymph Node
CD28
IL-2
Harlin et al, 2009; Gajewski et al, 2006.
27. Immunization Modalities
Antigen delivery strategy
– Targeting endogenous APCs
• Synthetic peptides or protein in adjuvant
• Recombinant viruses, bacteria
• Irradiated tumor transfectants
• Antigen/antibody complexes
• Antigen/TLR ligand fusions
• Plasmids (CpG oligonucleotides)
– Ex vivo loaded APCs
• Peptide, protein, tumor lysates, etc.
Additional modulators
– Cytokines, adjuvants, modulatory antibodies
28. Induction of Specific CTL Responses in Mice Using
Tumor Antigen Peptide-Loaded PBMC + IL-12
PBMC-P1A PBMC-P1A + IL-12 PBMC + IL-12 PBS
Percent Specific Lysis
E:T Ratio
PBMC = peripheral blood mononuclear cells; IL-12 = interleukin-12.
Fallarino et al, 1999.
29. Resolution of Subcutaneous Metastases
Following Immunization With MelanA
Peptide-Pulsed PBMC + rhIL-12
After 3 Vaccines After 9 Vaccines
ORR ~ 10%, With Another 20% SD
rhIL-12 = recombinant human IL-12; ORR = overall response rate; SD = stable disease.
Peterson et al, 2003.
30. Vaccination of Patients With Multiple Melanoma
Antigen Peptides + IL-12 Can Induce High Levels
of Functional Specific T Cells in the Blood
However, only a minority of patients (10%) have clinical responses.
(Why? – We will return to this question later [predictive biomarkers])
Peterson et al, 2003.
31. Model for CD8+ T-Cell-Mediated Anti-Tumor
Immune Response In Vivo: Interventions (cont.)
Blockade of
suppression
MHC I MHC II Immature DC
Migration From
Tumor
Vaccines
Tumor granzymes
TCR
eCD8
B7
Costimulation
APC
Mature DC Cytokines
Chemokines
Lymph Node
eCD8
nCD8 Migration From
Migration to
Lymph Node Lymph Node
CD28
IL-2
Harlin et al, 2009; Gajewski et al, 2006.
32. CTLA-4 Blockade for
Immunopotentiation
CTLA-4 is receptor induced on activated T cells
Ligation inhibits T cell activation
CTLA-4 deficient mice develop autoimmunity dominant role
is negative
Two defined ligands expressed largely on APC populations:
B7-1 and B7-2
Neutralizing mAbs against CTLA-4 augment T-cell activation
and promote tumor rejection in several mouse models
Two anti-CTLA-4 mAbs explored in clinical trials
Ipilimumab approved by FDA in 2011
CTLA-4 = cytotoxic T lymphocyte antigen-4; mAbs = monoclonal antibodies.
Pardoll, 2012; YervoyTM prescribing information, 2012.
33. CTLA-4 Is a Negative Regulator
of T-Cell Activation
Resting T Cell Activated T Cell
B7 B7
CD28 CD28
T Cell TCR APC T Cell TCR APC
CTLA4 B7
Pardoll, 2012; Korman et al, 2006.
34. Randomized Study of Vaccine Vs. Ipilimumab
Vs. Combination in Advanced Melanoma
Ipi = ipilimumab.
Hodi et al, 2010.
35. Clinical Response in Melanoma With
Single Agent Anti-CTLA-4 mAb
Screening Week 12: Progression
Week 20: Regression Week 36: Still Regressing
Wolchok et al, 2008.
36. T-Cell Infiltration in Skin and Gut
Following Anti-CTLA-4 mAb Treatment
Sarnaik et al, 2009.
37. Model for CD8+ T-Cell-Mediated Anti-Tumor
Immune Response In Vivo: Interventions (cont.)
Blockade of
suppression
MHC I MHC II Immature DC
Migration From
Tumor
Vaccines
Tumor granzymes
TCR
eCD8
B7
Costimulation
APC
Mature DC Cytokines
Chemokines
Lymph Node
eCD8
nCD8 Migration From
Migration to
Lymph Node Lymph Node
CD28
IL-2
Harlin et al, 2009; Gajewski et al, 2006.
39. Modified gp100 Peptide in Montanide
+/- Exogenous IL-2
Additional 19 patients treated with high-dose IL-2
after gp100 209M vaccination
In this study, 8 patients (42%) showed objective
tumor regression
Suggests IL-2 may help expand relevant T cells or
support their trafficking
Caveat: Effect of IL-2 alone?
Rosenberg et al, 1998.
40. High-Dose IL-2 ± Peptide Vaccine Phase III
Schwartzentruber et al, 2011.
41. Model for CD8+ T-Cell Mediated Anti-
Tumor Immune Response In Vivo (cont.)
MHC I MHC II Immature DC
Migration From
Tumor
Tumor granzymes
TCR
eCD8
B7
APC
Mature DC
Adoptive T-cell
therapy
eCD8
nCD8 Migration From
Migration to
Lymph Node Lymph Node
CD28
IL-2
Harlin et al, 2009; Gajewski et al, 2006.
42. Adoptive T-Cell Therapy
T cells are isolated, from
tumor site or generated in vitro Adoptive
transfer
Ex vivo enrichment and into
expansion of antigen-specific patient In vitro
effector T cells expansion
and
activation
T cells are reintroduced back
to the patient
T cells
Usually the patient is isolated
“conditioned” first with lympho from
depleting chemotherapy or patient
other agents
Yee, 2009.
43. TIL Therapy for Melanoma:
Rosenberg Approach
Tumor harvested, TILs collected and expanded
for infusion
In interim, patients receive lymphoablative
chemotherapy to “make space”
T cells are transferred and patients are given IL-2
Results: 6 of 13 patients responded
TILs = tumor-infiltrating lymphocytes.
Dudley et al, 2003.
44. Phase II Trial: Adoptive-Cell Therapy
• Stage IV melanoma (N = 35)
• Received autologous, tumor-
reactive, expanded tumor-
infiltrating lymphocytes + IL-2
after
lymphodepleting conditioning
with
cyclophosphamide and
fludarabine
• Results
– 3 CR; 15 PR (RR: 51%;
DOR: 11.5 mos)
– Adoptively transferred CTLs
persisted in several patients
> 1 year
• > 50% RR has held up with
further studies
CR = complete response; PR = partial response; RR = response rate; DOR = duration of response.
Dudley et al, 2005.
45. Model for CD8+ T-Cell-Mediated Anti-Tumor
Immune Response In Vivo: Interventions (cont.)
Blockade of
suppression
MHC I MHC II Immature DC
Migration From
Tumor
Vaccines
Tumor granzymes
TCR
eCD8
B7
Costimulation
APC
Mature DC Cytokines
Chemokines
Lymph Node
eCD8
nCD8 Migration From
Migration to
Lymph Node Lymph Node
CD28
IL-2
Harlin et al, 2009; Gajewski et al, 2006.
46. Hypothesis
Clinical benefit when it does occur with potent cancer vaccines
(and other immunotherapies) has generally not correlated with
T cell responses as measured in the blood
Features of the tumor microenvironment could dominate at the
effector phase of the anti-tumor T-cell response
– T-cell trafficking into tumor
– Immune suppressive mechanisms at tumor site
– Tumor cell biology and susceptibility to immune-mediated killing
– Complexities of the tumor stroma (vasculature, fibrosis)
Reasoned these features could be interrogated through pre-
treatment gene expression profiling of tumor site in each individual
patient
Such an analysis could identify a predictive biomarker profile
associated with clinical response, and also highlight new biologic
barriers that need to be overcome to optimize therapeutic efficacy
of vaccines
Gajewski et al, 2009.
47. Expression of a Subset of Chemokine Genes Is
Associated With Presence of CD8 Transcripts
CD8b
CCL2
CCL4
CCL5
CXCL9
CXCL10
CCL19
CCL21
Harlin et al, 2009.
Editor's Notes
Figure 2. T cell and dendritic cell interaction in draining lymph nodes.
Figure 2. T cell and dendritic cell interaction in draining lymph nodes.
Phase I trial of ipilimumab (IPI) alone and in combination with radiotherapy (XRT) in patients with metastatic castration resistant prostate cancer (mCRPC). Beer TM, et al. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2008;26(15S): Abstract 5004.
From Jedd ’s article: A male patient aged 52 years from study 2 had resection of an isolated retroperitoneal metastasis in 2004 and then developed recurrent disease in visceral lymph nodes and soft tissue in 2006. He was treated with high-dose IL-2, but unfortunately, after 2 cycles of therapy, a computed tomography (CT) scan performed in July revealed progression of disease. Ipilimumab was started in November 2006, at which time he had soft tissue disease of the chest wall and pelvis, retroperitoneal metastasis, and iliac nodal disease. The patient exhibited PD on clinical exam through week 10 of ipilimumab administration with discomfort due to enlargement of an axillary mass. Radiographic analysis at week 12 in fact revealed enlargement of multiple subcutaneous masses. However, when the patient was examined a few days later at his week 12 visit, he reported shrinkage of his palpable tumors in the axilla and abdominal wall and this was confirmed on physical exam. These radiographic and clinical findings are consistent with an initial increase in tumor size through week 10 followed by a decrease in size. The initial tumor enlargement was suspected to be caused by inflammation. The only toxicity he experienced was a mild erythematous rash and discomfort at the site of the axillary mass, perhaps related to inflammation. The patient received 4 doses of induction on study 2, but was then taken off study at week 12 for progression of disease. He was then enrolled on study 3, where he has exhibited slow regression of palpable lesions through 4 additional doses of ipilimumab given as re-induction therapy, reached a partial response (PR) at week 31 and his PR is ongoing now at week 48 after initial ipilimumab therapy. He continues to receive maintenance dosing q12wk.
Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med . 2004;351:1502-1512.
Outline: 1) Brief history of immunotherapy, which is really a history of single agent immunotherapy. 2) A. Introduce immunological checkpoints and checkpoint blockade describing interesting data on the potential for single agent efficacy 3) New data showing how conventional therapy, especially radiotherapy can have immunological effects 4) Show some data on combination immunotherapy which is the future
Haraoka et al, British Journal Cancer 2006: 94:275-80 (Japan) Kaplan – Meier analysis of overall survival according to the simultaneous presence of high levels of infiltrating CD8þ T cells and CD4þ T cells in cancer stroma in patients with NSCLC.
Ruffini et al, Annals Thorcic Surgery 2009; 87:365-72 (Italy) Survival according to the presence or absence of tumor-infiltrating lymphocytes (TIL) in total population of patients with lung neoplasms who underwent resection (p = 0.20).
Kawai et al, Cancer 2008; 113:1387-95 (Japan) Kaplan-Meier analysis of overall survival is shown according to distribution in 4 groups of macrophages and CD81 T cells. Patients whose tumors contained macrophages in the nest and more CD81 T cells in the nest had significantly better survival (macrophages, nest > stroma; CD81 T cells, nest > stroma) than patients with macrophages nest > stroma and CD81 T cells nest < stroma (P 5 .0070), patients with macrophages nest < stroma and CD81 T cells nest > stroma (P 5 .0010), and patients with macrophages nest < stroma and CD81 T cells: nest < stroma (P < .0001).
Dieu-Nosjean et al, JCO 2008, 26: 4410-17 (France) Evaluation of DC-Lamp as a marker of tumor-induced bronchus- associated lymphoid tissue (Ti-BALT) and its prognostic value. Kaplan-Meier curves of disease-free survival for 74 patients with non–small-cell lung cancer depending on the density of tumor-infiltrating DC-Lamp+ mature DC.
Al-Shibli et al, Histopathology 2009, 55: 301-12 (Norway)Disease-specific survival curves for stromal CD56+ cells in NSCLC.
Immunologic synapse. Target recognition by T cells is two-step process. Specific interaction of T-cell receptor (TCR) with major histocompatibility complex (MHC) –peptide complexes displayed by tumor cells or antigen-presenting cells (APCs; eg, dendritic cells) provides first signal for T-cell recognition. Second event is coregulatory signal that determines whether T cell will become activated or anergic (nonreactive). T-cell coreceptors transmitting stimulatory (+) or inhibitory (-) signals on engagement of specific ligands expressed by tumor cells or APCs are depicted. Molecules in B7-CD28 and tumor necrosis factor receptor (TNFR) families are now being targeted for cancer immunotherapy.
PD-1 and CTLA-4 play distinct roles in regulating T cell immunity. CTLA-4 modulates the early phases of activation of naı¨ve or memory T cells in response to TCR stimulation by MHC-peptide complexes displayed by antigen presenting cells ( ‘signal 1’). In contrast, PD-1 is expressed on antigenexperienced T cells in the periphery, and serves to limit the activity of T cells at the time of an inflammatory response, thereby protecting normal tissues from collateral destruction.
Two cohorts: NSCLung and Small Cell ED Lynch et al, WCLC 2011, ESMO 2010, Reck et al WCLC 2011
Lynch et al, WCLC 2011, ESMO 2010, Reck et al WCLC 2011
Lynch et al, WCLC 2011, ESMO 2010, Reck et al WCLC 2011 Phased schedule significantly improved mWHOPFS • No significant improvement for concurrent schedule The study met its primary endpoint of significantly improved irPFS in NSCLC for the Phased-ipilimumab regimen Significant improvement in mWHO-PFS and a trend for improved OS Subset analysis appeared to show greater efficacy in squamous than non-squamous patients with Phased-ipilimumab Small sample size warrants caution in interpretation Safety profile in this trial generally consistent with previous ipilimumab studies Safety profiles for squamous and non-squamous appeared similar No apparent exacerbation of toxicities seen with chemotherapy alone Adverse events generally manageable using protocol-defined treatment guidelines Kaplan-Meier Plots for progression-free survival per modified WHO criteria (mWHO-PFS). Per modified WHO criteria (mWHO), a reduction in index lesions by ≥ 25% or any new lesions (measurable or not) or a progression of nonindex lesions were considered an mWHO progression. mWHO-PFS was defined as the time from random assignment to mWHO progression (as determined by an independent radiologic review committee) or death. As indicated by symbols, patients who neither progressed nor died were censored on the date of last tumor assessment. P values were based on an unstratified log-rank test with a one-sided a of 0.1. HR, hazard ratio; Ipi, ipilimumab. (A) Control v phased Ipi.
Lynch et al, WCLC 2011, ESMO 2010, Reck et al WCLC 2011
Lynch et al, WCLC 2011, ESMO 2010, Reck et al WCLC 2011 Phased ipilimumab + chemotherapy appeared to show improved efficacy in first-line ED-SCLC vs. chemotherapy alone Improvement in irPFS Numerically higher irBORR Trend for improved OS Concurrent-ipilimumab regimen showed no such activity Safety profile in this trial generally consistent with previous ipilimumab studies Ipilimumab did not appear to exacerbate toxicities observed with chemotherapy alone Adverse events were generally manageable using protocol-defined treatment guidelines Results of this study support further investigation of the phased-ipilimumab regimen in previously untreated ED-SCLC
Konishi et al, Clinical Cancer Research 2004; 10:5094-100 Representative immunohistochemical staining in B7-H1-posi tive tumor regions (A) and B7-H1-negative tumor regions (B) on the same non-small cell lung cancer sections. On consecutive tumor sections, TILs were identified by CD45 staining (C and D), and PD-1 expression was identified immunohistochemically (E and F). A low proportion of TILs in B7-H1-positive tumor regions is shown in C. A high proportion of TILs in B7-H1-negative tumor regions is shown in D. Expression of PD-1 is lower on TILs in B7-H1-positive tumor regions (E) compared with that on TILs in B7-H1-negative tumor regions (F). Scale bar, 100 um.
Brahmer, Drake, Powderly, Topalian et al, JCO 2010 28:3167
Brahmer, Drake, Powderly, Topalian et al, JCO 2010 28:3167
ASCO 2012, Brahmer J, et al Chart subscripts: a= Response evaluable patients. B = CR or PR = OR C= unconfirmed PR D= Response rate (OR +uPR) / n
This patient is still in a durable partial remission at 3 years later
T. De Pas, et al , Critical Reviews in Oncology/Hematology, 2012 (Italy) L-BLP25 = Stimuvax; EGF = CIMAvax; belagenpumatucel-1 = Lucanix survival; tumor-free, overall, pro-gression free (STOP) trial in NSCLC. Here the vaccine is made up of four NSCLC cell lines that are engineered to express an anti-sense to TGF- 2 that decreases the expres- sion of this immunosuppressive cytokine [49]. The results of the phase II trial were encouraging demonstrating safety of the patients and some clinical response. The results of the phase III trial are expected in October 2011[50]. MAGE-A3 (melanoma associated antigen A3) expressed in 35-48%% of NSCLC ’s AS15 Adjuvant = A vaccine adjuvant containing CpG 7909, monophosphoryl lipid, and QS-21 with potential antineoplastic and immunostimulatory activities. CpG 7909 is a synthetic 24-mer oligonucleotide containing 3 CpG motifs that selectively targets Toll-like receptor 9 (TLR9), thereby activating dendritic and B cells and stimulating cytotoxic T cell and antibody responses against tumor cells bearing tumor antigens. Monophosphoryl lipid is a detoxified derivative of lipid A, a component of Salmonella minnesota lipopolysaccharide (LPS); this agent may enhance humoral and cellular responses to various antigens. QS-21 is a purified, naturally occurring saponin derived from the South American tree Quillaja saponaria Molina and exhibits various immunostimulatory activities. Combinations of monophosphoryl lipid and QS-21 may be synergistic in inducing humoral and cellular immune responses. Check for active clinical trials or closed clinical trials using this agent. ( NCI Thesaurus) About half of all NSCLC patients whose tumours have been completely removed by surgery have a recurrence within two years. A phase II trial of the MAGE-A3 ASCI in these patients with completely resected NSCLC expressing MAGE-A3 showed 25% fewer recurrences among patients at the final analysis, and the difference between the two arms has held now for almost six years. The phase III trial, which aims to enrol around 2300 NSCLC patients positive for the MAGE-A3 antigen – “the largest lung cancer trial ever conducted in the adjuvant setting” – is being carried out using a ‘new and improved’ immunological adjuvant, which GSK hopes will give even better results.
R. Sangha, C. Butts, Clinical Cancer Research 2007; 13:4652-54 an open-label randomized phase II trial was undertaken (21). Patients with stable disease or responding stage IIIB or IV NSCLC after any first-line chemotherapy were randomly assigned to either L-BLP25 plus best supportive care or best supportive care alone. Patients in the L-BLP25 arm received a single i.v. dose of cyclophosphamide (300 mg/m2)followed by eight weekly s.c. immunizations of L-BLP25 (1,000 A g). Subsequent immunizations were administered at 6-week intervals. Updated survival analysis, with median follow-up of 53 mo, for stage IIIB locoregional patients.Median survival 30.6mo (mo) for L-BLP25^ treated patients, and 13.3 mo for best supportive care (BSC).
R. Ramlau et al, Journal of Thoracic Oncology, 2008;3: 735-44 A multicenter, randomized phase II study has explored two schedules of the combination of TG4010 with first line chemotherapy in patients with stage IIIB/IV non-small cell lung cancer. In Arm 1, TG4010 was combined upfront with cisplatin (100 mg/m2 day 1) and vinorelbine (25 mg/m2 day 1 and day 8). In Arm 2, patients were treated with TG4010 monotherapy until disease progression, followed by TG4010 plus the same chemotherapy as in Arm1. Response rate was evaluated according to RECIST. Median time to progression and median overall survival were calculated according to the Kaplan–Meier method. Results: Sixty-five patients were enrolled, 44 in Arm 1 and 21 in Arm 2, in accordance with the two stage Simon design of the statistical plan. In Arm 1, partial response was observed in 13 patients out of 37 evaluable patients (29.5% of the intent to treat population, 35.1% of the evaluable patients). In Arm 2, two patients experienced stable disease for more than 6 months with TG4010 alone (up to 211 days), in the subsequent combination with chemotherapy, one complete and one partial response were observed out of 14 evaluable patients. Arm 2 did not meet the criteria for moving forward to second stage. The median time to progression was 4.8 months for Arm 1. The median overall survival was 12.7 months for Arm 1 and 14.9 for Arm 2. One year survival rate was 53% for Arm 1 and 60% for Arm 2. TG4010 was well tolerated, mild to moderate injection site reactions, flu-like symptoms, and fatigue being the most frequent adverse reactions. A MUC1-specific cellular immune response was observed in lymphocyte samples from all responding patients evaluable for immunology. Conclusions: The combination of TG4010 with standard chemotherapy in advanced non-small cell lung cancer is feasible and shows encouraging results. A randomized study evaluating the addition of TG4010 to first line chemotherapy in this population is in progress OS according to cellular immune response against MUC1 for the whole study population. Patients with (-------) or without (——) MUC1-specific ELISpot at any timepoint. O = complete data, + = censored. Differences between the 2 populations are statistically significant with p = 0.001.
E Vinageras, et al, JCO 2008; 26: 1452-58 (Cuba) Survival functions for patients younger than 60 years (vaccinated, n = 22; controls, n = 28; log-rank P = .0124).
MAGE-A3 (melanoma associated antigen A3) expressed in placenta and testes, not in normal cells, but + in 35-48%% of NSCLC ’s AS15 Adjuvant = A vaccine adjuvant containing CpG 7909, monophosphoryl lipid, and QS-21 with potential antineoplastic and immunostimulatory activities. CpG 7909 is a synthetic 24-mer oligonucleotide containing 3 CpG motifs that selectively targets Toll-like receptor 9 (TLR9), thereby activating dendritic and B cells and stimulating cytotoxic T cell and antibody responses against tumor cells bearing tumor antigens. Monophosphoryl lipid is a detoxified derivative of lipid A, a component of Salmonella minnesota lipopolysaccharide (LPS); this agent may enhance humoral and cellular responses to various antigens. QS-21 is a purified, naturally occurring saponin derived from the South American tree Quillaja saponaria Molina and exhibits various immunostimulatory activities. Combinations of monophosphoryl lipid and QS-21 may be synergistic in inducing humoral and cellular immune responses. Check for active clinical trials or closed clinical trials using this agent. ( NCI Thesaurus) About half of all NSCLC patients whose tumours have been completely removed by surgery have a recurrence within two years. A phase II trial of the MAGE-A3 ASCI in these patients with completely resected NSCLC expressing MAGE-A3 showed 25% fewer recurrences among patients at the final analysis, and the difference between the two arms has held now for almost six years (but the disease free interval and DFS were not statistically significant). The phase III trial, which aims to enrol around 2300 NSCLC patients positive for the MAGE-A3 antigen – “the largest lung cancer trial ever conducted in the adjuvant setting” – is being carried out using a ‘new and improved’ immunological adjuvant, which GSK hopes will give even better results.
Left image: Right image: Immunohistochemical stains of renal cancer tissue using the MN-75 anti-CAIX antibody representative of high CAIX staining. Table: The proposed new model for combining pathology predictive group with CAIX staining. Three pathologic risk groups previously reported by Upton et al. can theoretically be collapsed into two groups having distinct response rates to IL-2 therapy and survivals.
Hodi et al, DFHCC Melanoma Phase I, ASCO 2011 #8511
As per previous slide, but with MDSC this time
Figlin et al, 2012 – ASCO. Presented at the Genitourinary Cancers Symposium.
Figlin et al, 2012 – ASCO. Presented at the Genitourinary Cancers Symposium.
IMA091 is a vaccine comprised of multiple RCC tumor-associated peptides
Slide 22
Synthroid = levothyroxine sodium tablets, USP
While 1, 2 and 4 are wrong the rest or not either wrong or right. Ask panel which they favor also ask if they use nomograms to assess risk.
Again no “right answer” 5 will be wrong. To some extent 3 and 4 will be wrong. Ask panel which they favor – extent of postive margin, number of LN
Again no “right answer”
Point is that patient now has CRPC. Is definition the same everywhere?
Again no right answer in my mind – with the clear issue that nothing is approved in this space. Thoughts?
Point is that patient now has CRPC. Is definition the same everywhere?